Cutaneous Granulomas: Mechanisms, Cellular Interactions, and Therapeutic Insights

Abstract Granulomas are specialized biological defense mechanisms that form in response to infections with pathogens, foreign bodies, or specific stimuli such as antimicrobials or fungi. These structures function to isolate foreign materials and pathogens that cannot be eliminated by immune cells, primarily through macrophage activity. In the skin, granulomas are a hallmark of several conditions, including sarcoidosis, granuloma annulare, tuberculosis and leprosy, each exhibiting distinct pathological and immunological features. Granulomas can also arise from lipid accumulation, as observed in xanthogranuloma, or be triggered by inflammatory processes associated with unidentified antigens. Among their cellular components, Langhans-type multinucleated giant cells play a pivotal role in granuloma structure and function, contributing to pathogen containment and tissue remodeling, though their precise mechanisms of action remain an area of active investigation. In addition to these giant cells, recent studies have identified TREM2-positive macrophages as key contributors to granuloma formation and maintenance. These macrophages are involved in extracellular degradation of foreign substances and play a role in adapting to the hypoxic and nutrient-poor microenvironment of granulomas through metabolic reprogramming, including the pentose phosphate pathway. Recent advances in molecular biology, such as single-cell RNA sequencing, have provided unprecedented insights into the cellular heterogeneity and molecular pathways involved in granuloma formation. These techniques have revealed disease-specific differences in immune cell profiles and activation states, offering new perspectives on the underlying mechanisms of granulomatous diseases. Despite these advances, the precise processes driving granuloma formation and their functional significance remain largely unclear. This review addresses the central question, “What is a granuloma? ” by synthesizing recent findings, with a particular focus on cutaneous granulomas, and presenting interpretations grounded in the current body of literature. Furthermore, we discuss the implications of these findings for the development of novel therapeutic strategies, including targeted immunomodulation and cytokine blockade, which hold promise for treating granulomatous diseases while preserving host defense.